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J. Biol. Chem., Vol. 284, Issue 2, 1106-1115, January 9, 2009

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Basal Levels of eIF2 Phosphorylation Determine Cellular Antioxidant Status by Regulating ATF4 and xCT Expression^*

From the Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037

eIF2 is part of a multimeric complex that regulates cap-dependent translation. Phosphorylation of eIF2 (phospho-eIF2) is induced by various forms of cell stress, resulting in changes to the proteome of the cell with two diametrically opposed consequences, adaptation to stress or initiation of programmed cell death. In contrast to the robust eIF2 phosphorylation seen in response to acute insults, less is known about the functional role of basal levels of eIF2 phosphorylation. Here we show that mouse embryonic fibroblasts expressing a nonphosphorylatable eIF2 have enhanced sensitivity to diverse toxic insults, including amyloid β-(1–42) peptide (Aβ), a key factor in the pathogenesis of Alzheimer disease. This correlates with impaired glutathione metabolism because of down-regulation of the light chain, xCT, of the cystine/glutamate antiporter system X^-_c. The mechanistic link between the absence of phospho-eIF2 and xCT expression is nuclear factor ATF4. Consistent with these findings, long term activation of the phospho-eIF2/ATF4/xCT signaling module by the specific eIF2 phosphatase inhibitor, salubrinal, induces resistance against oxidative glutamate toxicity in the hippocampal cell line HT22 and primary cortical neurons. Furthermore, in PC12 cells selected for resistance against Aβ, increased activity of the phospho-eIF2/ATF4/xCT module contributes to the resistant phenotype. In wild-type PC12 cells, activation of this module by salubrinal ameliorates the response to Aβ. Furthermore, in human brains, ATF4 and phospho-eIF2 levels are tightly correlated and up-regulated in Alzheimer disease, most probably representing an adaptive response against disease-related cellular stress rather than a correlate of neurodegeneration.

Received for publication, September 22, 2008 , and in revised form, November 10, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant AG025337 (to P. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported by Fellowship LE1846/2-1 from the Deutsche Forschungsgemeinschaft. Present address: Dept. for Neurology, University Medical Center Hamburg-Eppendorf, Martinstrasse 52, 20246 Hamburg, Germany.

² To whom correspondence should be addressed: Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-453-4100, ext. 1932; Fax: 858-535-9062; E-mail: pmaher{at}salk.edu.

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